Process for preparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds

ABSTRACT

The invention relates to processes and intermediates for preparing compounds of formula I: 
     
       
         
         
             
             
         
       
     
     where a, R 1 , and R 3-6  are as defined in the specification, or a salt thereof. The compounds of formula I are serotonin and norepinephrine reuptake inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/114,541, filed on Nov. 14, 2008; the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to processes and intermediates forpreparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds havingactivity as serotonin (5-HT) and norepinephrine (NE) reuptakeinhibitors.

2. State of the Art

Pain is an unpleasant sensory and emotional experience associated withactual or potential tissue damage, or described in terms of such damage(International Association for the Study of Pain (IASP), PainTerminology). Chronic pain persists beyond acute pain or beyond theexpected time for an injury to heal (American Pain Society. “PainControl in the Primary Care Setting.” 2006:15). Neuropathic pain is paininitiated or caused by a primary lesion or dysfunction in the nervoussystem. Peripheral neuropathic pain occurs when the lesion ordysfunction affects the peripheral nervous system and centralneuropathic pain when the lesion or dysfunction affects the centralnervous system (IASP).

Several types of therapeutic agents are currently used to treatneuropathic pain including, for example, tricyclic antidepressants,serotonin and norepinephrine reuptake inhibitors, calcium channelligands (e.g., gabapentin and pregabalin), topical lidocaine, and opioidagonists (e.g., morphine, oxycodone, methadone, levorphanol andtramadol).

The 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds describedherein inhibit the reuptake of both serotonin and norepinephrine bybinding to the serotonin and norepinephrine transporters. A need existsfor an efficient process of preparing such compounds.

SUMMARY OF THE INVENTION

The present invention provides novel intermediates and processes forpreparing compounds that have been found to possess serotonin reuptakeinhibitory activity and norepinephrine reuptake inhibitory activity.

One aspect of the invention relates to a process for preparing acompound of formula I:

or a salt thereof, where: a is 0, 1, 2, 3, or 4; each R¹ isindependently halo or trifluoromethyl; R³ is hydrogen, halo, or—C₁₋₆alkyl; R⁴, R⁵, and R⁶ are independently hydrogen or halo; theprocess comprising the steps of:

(a) reacting a compound of formula 1:

or a salt thereof, with a compound of formula 2:

in the presence of a base, to provide a compound of formula 3:

or a salt thereof, where L is a leaving group and P is anamino-protecting group; and

(b) removing the amino-protecting group, P, from the compound of formula3 or a salt thereof, to provide a compound of formula I or a saltthereof.

In one embodiment, the compound of formula I is4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine or apharmaceutically acceptable salt thereof. In another embodiment, thecompound of formula I is defined as:

(a) R³ and R⁵ are hydrogen and:

-   -   (i) R⁴ is fluoro, R⁶ is fluoro, and a is 0;    -   (ii) R⁴ is fluoro, R⁶ is fluoro, a is 1, and R¹ is 4-fluoro,        5-fluoro, 5-trifluoromethyl, or 6-fluoro;    -   (iii) R⁴ is fluoro, R⁶ is fluoro, a is 2, and R¹ is        4,5-difluoro, 4,6-difluoro, or 5,6-difluoro;    -   (iv) R⁴ is fluoro, R⁶ is chloro, and a is 0;    -   (v) R⁴ is chloro, R⁶ is fluoro, and a is 0; or    -   (vi) R⁴ is bromo, R⁶ is chloro, and a is 0; or

(b) R³ and R⁴ are hydrogen, R⁵ is fluoro, R⁶ is chloro, and:

-   -   (i) a is 0;    -   (ii) a is 1 and R¹ is 5-fluoro or 6-fluoro; or    -   (iii) a is 2 and R¹ is 4,6-difluoro; or

(c) R⁴ and R⁵ are hydrogen, R⁶ is fluoro and;

-   -   (i) R³ is fluoro and a is 0;    -   (ii) R³ is fluoro, a is 1, and R¹ is 3-fluoro, 5-fluoro,        5-trifluoromethyl, or 6-fluoro;    -   (iii) R³ is fluoro, a is 2, and R¹ is 4,6-difluoro; or    -   (iv) R³ is chloro or methyl, and a is 0; or

(d) R³, R⁴, and R⁵ are hydrogen and:

-   -   (i) R⁶ is H, and a is 0;    -   (ii) R⁶ is H, a is 1, and R′ is 5-fluoro or 6-fluoro;    -   (iii) R⁶ is fluoro and a is 0;    -   (iv) R⁶ is fluoro, a is 1, and le is 4-fluoro, 5-fluoro, or        6-fluoro;    -   (v) R⁶ is fluoro, a is 2, and R¹ is 4,5-difluoro or        4,6-difluoro;    -   (vi) R⁶ is chloro and a is 0;    -   (vii) R⁶ is chloro, a is 1, and R¹ is 4-fluoro, 6-fluoro, or        5-trifluoromethyl;    -   (viii) R⁶ is chloro, a is 2, and R¹ is 4,5-difluoro; or    -   (ix) R⁶ is bromo and a is 0;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a process for preparing acompound of formula 1 or a salt thereof, the process comprising thesteps of:

(a′) reacting a compound of formula 4:

or a salt thereof, with a reducing agent to provide a compound offormula 5:

or a salt thereof; and

(b′) converting the hydroxyl group of the compound of formula 5 or asalt thereof, into a leaving group, L, to provide a compound of formula1 or a salt thereof.

Still another aspect of the invention relates to a novel intermediatesused in the processes of the invention. In one such aspect of theinvention novel intermediates have formula 1:

or a salt thereof, where: L is bromo, iodo, or —OS(O₂)—R, where R is—C₁₋₄alkyl or phenyl, and the phenyl is optionally substituted with—C₁₋₄alkyl, halo or nitro; a is 0, 1, 2, 3, or 4; each R¹ isindependently halo or trifluoromethyl; and P is an amino-protectinggroup.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel processes for preparing compounds offormula I:

and compounds of formula 1:

or a salt thereof.

The integer “a” is 0, 1, 2, 3, or 4. In one particular embodiment, a is0 (i.e., R¹ is absent), 1, or 2. Each R¹ moiety is independently halo ortrifluoromethyl. The R³ moiety is hydrogen, halo, or —C₁₋₆alkyl. EachR⁴, R⁵, and R⁶ moiety is independently hydrogen or halo. In oneparticular embodiment, a is 0. In another embodiment, a is 0, R³ and R⁵are hydrogen, and R⁴ and R⁶ are fluoro.

DEFINITIONS

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated. Additionally, as used herein, the singular forms“a,” “an” and “the” include the corresponding plural forms unless thecontext of use clearly dictates otherwise. The terms “comprising”,“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements. Allnumbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth used herein are tobe understood as being modified in all instances by the term “about,”unless otherwise indicated. Accordingly, the numbers set forth hereinare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each number should at least be construed in lightof the reported significant digits and by applying ordinary roundingtechniques.

The compounds described herein have typically been named using theAutoNom feature of the commercially-available MDL® ISIS/Draw software(Symyx, Santa Clara, Calif.). Typically, compounds of formula I havebeen named as 4-[2-(2-fluorophenoxymethyl)phenyl]piperidines. Numberingof the compounds described herein is as follows:

As used herein, the phrase “having the formula” or “having thestructure” is not intended to be limiting and is used in the same waythat the term “comprising” is commonly used.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₂alkyl, —C₁₋₃alkyl, —C₁₋₄alkyl, —C₁₋₆alkyl, and —C₁₋₈alkyl.Representative alkyl groups include, by way of example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, where the carbon atoms are in anyacceptable configuration.

The term “halo” means fluoro, chloro, bromo and iodo.

As used herein, the phrase “of the formula”, “having the formula” or“having the structure” is not intended to be limiting and is used in thesame way that the term “comprising” is commonly used.

The term “salt” when used in conjunction with a compound means a salt ofthe compound derived from an inorganic or organic base or from aninorganic or organic acid. In addition, when a compound of formula Icontains both a basic moiety, such as an amine, and an acidic moietysuch as a carboxylic acid, zwitterions may be formed and are includedwithin the term “salt” as used herein. Salts derived from inorganicbases include aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, manganous, potassium, sodium, zinc, andthe like. Particularly preferred are ammonium, calcium, magnesium,potassium and sodium salts. Salts derived from organic bases includesalts of primary, secondary and tertiary amines, including substitutedamines, cyclic amines, naturally-occurring amines, and the like, such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. Salts derived from inorganicacids include salts of boric, carbonic, hydrohalic (hydrobromic,hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamicand sulfuric acids. Salts derived from organic acids include salts ofaliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic,lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids(e.g., acetic, butyric, formic, propionic and trifluoroacetic acids),amino acids (e.g., aspartic and glutamic acids), aromatic carboxylicacids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic,hippuric, and triphenylacetic acids), aromatic hydroxyl acids (e.g.,o-hydroxybenzoic, p-hydroxybenzoic, 1-hydroxynaphthalene-2-carboxylicand 3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylicacids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic,mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids(e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic,isethionic, methanesulfonic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic andp-toluenesulfonic acids), xinafoic acid, and the like. Particularlypreferred are citric, hydrobromic, hydrochloric, maleic, phosphoric,sulfuric and tartaric acids. The term “pharmaceutically acceptable salt”means a salt prepared from a base or an acid which is acceptable foradministration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). However, it isunderstood that the salts covered by the invention are not required tobe pharmaceutically acceptable salts, such as salts of intermediatecompounds that are not intended for administration to a patient.

All other terms used herein are intended to have their ordinary meaningas understood by those of ordinary skill in the art to which theypertain.

Process Conditions

Suitable inert diluents for use in the process of the invention include,by way of illustration and not limitation, organic diluents such asacetic acid, tetrahydrofuran (THF), acetonitrile (MeCN),N,N-dimethylformamide (DMF), N,N-dimethylacetamide,N-methylpyrrolidinonc, dimethyl sulfoxide (DMSO), toluene,dichloromethane (DCM), acetone, ethyl acetate, isopropyl acetate, methylt-butyl ether, chloroform (CHCl₃), carbon tetrachloride (CCl₄),1,4-dioxane, methanol, ethanol, propanol, isopropanol, butanol, ethyleneglycol, and the like. Aqueous diluents may also be used, and includewater as well as basic and acidic aqueous diluents. Combinations of anyof the foregoing diluents are also contemplated.

There are numerous bases that are suitable for use in the process of theinvention. Exemplary organic bases include, by way of illustration andnot limitation: amines including primary alkylamines (e.g., methylamine,ethanolamine, the buffering agent tris, and the like), secondaryalkylamines (e.g., dimethylamine, methylcthanolamine,N,N-diisopropylethylamine (DIPEA), and the like), tertiary amines (e.g.,trimethylamine, triethylamine, triethylenediamine, and the like);ammonia compounds such as ammonium hydroxide and hydrazine; alkali metalhydroxides such as sodium hydroxide, sodium methoxide, potassiumhydroxide, potassium t-butoxide, and the like; metal hydrides; andalkali metal carboxylate salts such as sodium acetate and the like).Exemplary inorganic bases, include, by way of illustration and notlimitation: alkali metal carbonates such as lithium carbonate, potassiumcarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, andthe like; other carbonates such as calcium carbonate and the like; andalkali metal phosphates such as potassium phosphate and the like).

All reactions are typically conducted at a temperature within the rangeof about −78° C. to about 110° C., for example at room temperature.Reactions may be monitored by use of thin layer chromatography (TLC),high performance liquid chromatography (HPLC), and/or LCMS untilcompletion. Reactions may be complete in minutes, may take hours,typically from 1-2 hours and up to 48 hours, or days, such as up to 3-4days.

Upon completion of any of the process steps, the resulting mixture orreaction product may be further treated in order to obtain the desiredproduct. For example, the resulting mixture or reaction product may besubjected to one or more of the following procedures: dilution (forexample with saturated NaHCO₃ or EtOAc); extraction (for example, withEtOAc, CHCl₃, DCM, aqueous HCl); washing (for example, with DCM, 1.0 MNaOH in water, saturated aqueous NaCl, or saturated NaHCO₃);distillation; drying (for example, over MgSO₄ or Na₂SO₄, or in vacuo);precipitation; filtration; being redissolved (for example in a 1:1acetic acid:H₂O solution); purification (for example by preparativeHPLC, reverse phase preparative HPLC, or crystallization); and/orcrystallizing (for example, from EtOAc/ethanol or isopropanol/water);and/or being concentrated (for example, in vacuo).

The process for preparing a compound of formula I or a salt thereof isconducted in two steps. The first step of the process is a nucleophilicdisplacement coupling reaction, which involves combining the compound offormula 1 or a salt thereof with a 2-fluorophenol compound of formula 2in the presence of a base to form a compound of formula 3 or a saltthereof.

The compound of formula 1 and salts thereof can be prepared bytechniques that are known in the art of by the methods described herein.The 2-fluorophenol compound is either commercially available, or isreadily synthesized by techniques that are well known in the art.

In one embodiment, a slight excess of the 2-fluorophenol compound isused based on the amount of the compound of formula 1. In oneembodiment, from about 1.0 to about 2.0 equivalents of the2-fluorophenol compound are used, and in another embodiment, about 1.0to 1.5 equivalents are used.

Typically, the compound of formula 1 is dissolved in an inert diluent,then added to the 2-fluorophenol compound and a base. In one embodiment,an excess of base is used based on the amount of the compound offormula 1. In one embodiment, from about 2.0 to about 4.0 equivalents ofthe base are used, and in another embodiment, about 3.0 equivalents areused. In one embodiment, the base is an alkali metal carbonate, and inone particular embodiment, potassium carbonate. Exemplary inert diluentsinclude acetonitrile.

Formation of the compound of formula 3 or a salt thereof is typicallyconducted at a temperature ranging from about 40° C. to about 60° C.;and in one embodiment at a temperature ranging from about 45° C. toabout 55° C. for about 5 to about 24 hours. The reaction mixture is thenallowed to cool to room temperature.

When formation of compound of formula 3 or a salt thereof issubstantially complete, the supernatant can be separated from the baseand other solids and used in the next step. Alternately, the resultingproduct can be isolated and purified by conventional procedures prior tothe deprotection step.

The compound of formula 1 has a leaving group, which is depicted as “L”,which is a functional group or atom which can be displaced by anotherfunctional group or atom in a substitution reaction, such as anucleophilic substitution reaction. By way of example, representativeleaving groups include halogens (e.g., chloro, bromo and iodo groups);sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylateand the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy andthe like. Of particular interest are sulfonic ester groups, which can bedepicted by the formula —OS(O₂)—R, where R is —C₁₋₄alkyl or phenyl, andthe phenyl group may be substituted with —C₁₋₄alkyl, halo or nitro. Inone particular embodiment, the leaving group is —OS(O₂)—CH₃ or—OS(O₂)—4-methylphenyl.

The compounds of formula 1 and formula 3 have an amino-protecting group,which is depicted as “P”, which is a group covalently attached to theamino functional group that prevents the functional group fromundergoing undesired reactions but which permits the functional group tobe regenerated (i.e., deprotected or unblocked) upon treatment of theprotecting group with a suitable reagent. Representativeamino-protecting groups include, but are not limited to,t-butoxycarbonyl (Boc), trityl (Tr), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),t-butyldimethylsilyl (TBS), and the like. In one particular embodiment,the amino-protecting group is Boc. Other representative amino protectinggroups are described, for example, in T. W. Greene and G. M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York,1999.

The second step of the process is a deprotection step, which involvesremoving the amino-protecting group, P, from the compound of formula 3or a salt thereof, to provide a compound of formula I or a salt thereof.Standard deprotection techniques and reagents such as TFA (alone or inDCM) or HCl (in 1,4-dioxane or ethanol) are used to remove the P group.For example, a Boc group can be removed using an acidic reagent such ashydrochloric acid, trifluoroacetic acid, and the like; while a Cbz groupcan be removed by employing catalytic hydrogenation conditions such asH₂ (1 atm), 10% Pd/C in an alcoholic solvent.

Typically, the compound of formula 3 and the deprotecting reagent arecombined, optionally in an inert diluent. An excess amount of reagent isused. In one embodiment from about 5.0 to about 25.0 equivalents of thereagent are used based on the amount of the compound of formula 3; andin another embodiment from about 10.0 to about 20.0 equivalents of thereagent are used.

This deprotection step is typically conducted at a temperature rangingfrom about 10° C. to about 30° C.; and in one embodiment at atemperature ranging from about 15° C. to about 25° C. for about 20 toabout 28 hours, and in one embodiment for about 24 hours or overnight,or until the reaction is substantially complete. In one embodiment, thedeprotecting reagent is TFA or HCl in EtOH.

When formation of compound of formula I or a salt thereof issubstantially complete, the resulting product can then be isolated andpurified by conventional procedures. The compound of formula I may becrystallized by further treatment with ethyl acetate and ethanol, andoptionally recrystallized with isopropanol and water.

The process for preparing a compound of formula 1 or a salt thereof isconducted in two steps. The first step of the process is a boranereduction reaction, which involves combining one equivalent of acompound of formula 4 or a salt thereof with one or more equivalents ofa reducing agent to form a compound of formula 5 or a salt thereof.

Typically, the reducing agent is slowly added to a mixture of thecompound of formula 4 in an inert diluent such as tetrahydrofuran. Inone embodiment, about 1.5 to 2.5 equivalents of the reducing agent areused based on the amount of compound of formula 4; and in anotherembodiment, about 2.0 equivalents are used.

The compound of formula 4, for example,4-(2-carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (P=Boc),is commercially available. Suitable reducing agents include boranedimethyl sulfide complex, 9-borabicyclo[3.3.1]nonane, borane1,2-bis(t-butylthio)ethane complex, borane t-butylamine complex, boranedi(t-butyl)phosphine complex, borane-tetrahydrofuran complex and soforth. In one particular embodiment, the reducing agent is boranedimethyl sulfide complex or borane-tetrahydrofuran complex.

Formation of the compound of formula 5 is typically conducted at atemperature ranging from about 20° C. to about 70° C.; and in oneembodiment is briefly stirred at room temperature, then heated to about40° C. to 60° C., for a time period ranging from 40 to 120 minutes, andin one embodiment, 60 minutes, or until formation of the compound offormula 5 is substantially complete. The reaction is typically conductedunder nitrogen. When formation of the compound of formula 5 issubstantially complete, the reaction may be quenched, and the resultingproduct is then isolated and purified by conventional procedures.

The second step of the process involves converting the hydroxyl group ofthe compound of formula 5 or a salt thereof, into a leaving group, L, toprovide a compound of formula 1 or a salt thereof.

Typically one equivalent of a compound of formula 5 is combined with oneor more equivalents of a reagent suitable for converting the hydroxylgroup to a leaving group. In one embodiment, about 1.0 to 1.7equivalents of the reagent are used based on the amount of compound offormula 5; and in another embodiment, about 1.1 to about 1.5 equivalentsare used.

Formation of the formula 1 or a salt thereof is typically conducted at atemperature ranging from about −10° C. to about 10° C.; and in at about0° C., for a time period ranging from 40 to 120 minutes, and in oneembodiment, from 60 to 90 minutes, or until formation of the compound offormula 1 or a salt thereof is substantially complete. The reaction istypically conducted under nitrogen. When formation of the compound offormula 1 or a salt thereof is substantially complete, the resultingproduct is then isolated and/or purified by conventional procedures.

Suitable reagents for converting the hydroxyl group to a halogen leavinggroup include halogenating agents such as: thionyl chloride orphosphorus trichloride (where L=Cl); carbon tetrabromide (withtriphenylphosphine or potassium carbonate), hydrogen bromide, orphosphorus tribromide (where L=Br); cesium iodine (with aluminumtrichloride (((where L=I); and so forth.

Suitable reagents for converting the hydroxyl group to a sulfonic estergroup leaving group include p-toluenesulfonyl chloride (forming atosylate where L=—OS(O₂)-4-methylphenyl), methanesulfonic anhydride(forming a mesylate where L=—OS(O₂)—CH₃), p-bromobenzenesulfonylchloride (forming a brosylate where L=—OC(O)-4-bromophenyl),p-nitrobenzenesulfonyl chloride (forming a nosylate whereL=—OC(O)-4-nitrophenyl), and so forth. This reaction is typicallyconducted in a suitable base. In one embodiment, about 1.2 to 1.8equivalents of the base are used based on the amount of compound offormula 5; and in another embodiment, about 1.4 to 1.6 equivalents areused. Exemplary bases for use with such reagents include secondaryalkylamines such as N,N-diisopropylethylamine and tertiary amines suchas triethylenediamine.

Suitable reagents for converting the hydroxyl group to an acyloxy groupleaving group include acetyl chloride (where L=acetoxy or —OC(O)CH₃),trifluoroacetyl chloride (where L=trifluoroacetoxy —OC(O)CF₃), and soforth. Such reagents are typically used with an inert diluent such astetrahydrofuran.

In one embodiment the reagent for converting the hydroxyl group isp-toluenesulfonyl chloride or methanesulfonic anhydride. Additionaldetails of this reaction are described, for example, in Hartung et al.(1997) Synthesis 12:1433-1438.

Certain of the intermediates described herein are believed to be noveland accordingly, such compounds are provided as further aspects of theinvention including, for example, of formula 1:

or a salt thereof, where: L is bromo, iodo, or —OS(O₂)—R, where R is—C₁₋₄alkyl or phenyl, and the phenyl is optionally substituted with—C₁₋₄alkyl, halo or nitro; a is 0, 1, 2, 3, or 4; each R¹ isindependently halo or trifluoromethyl; and P is an amino-protectinggroup. In one particular embodiment, L is —OS(O₂)—R and R is methyl or4-methyl-phenyl; a is 0; and P is t-butoxycarbonyl.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of the invention. These specific embodiments,however, are not intended to limit the scope of the invention in any wayunless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard meaning:

-   -   AcOH acetic acid    -   Boc t-butoxycarbonyl    -   DCM dichloromethane (i.e., methylene chloride)    -   DIPEA N,N-diisopropylethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   IPA isopropyl alcohol    -   IPAc isopropyl acetate    -   MeCN acetonitrile (CH₃CN)    -   McOH methanol    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TsCl p-toluenesulfonyl chloride or 4-methylbenzenesulfonyl        chloride

Any other abbreviations used herein but not defined have their standard,generally accepted meaning. Unless noted otherwise, all materials, suchas reagents, starting materials and solvents, were purchased fromcommercial suppliers (such as Sigma-Aldrich, Fluka Riedel-de Haën, andthe like) and were used without further purification.

Preparation 14-[2-(Toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylic Acidt-Butyl Ester

4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g, 16mmol, 1.0 eq.) and THF (130 mL, 1.7 mol) were combined at roomtemperature under nitrogen. Borane dimethyl sulfide complex (2.9 mL, 33mmol, 2.0 eq.) was added dropwise and the mixture was stirred for 5minutes, then heated at reflux for 1 hour. The mixture was cooled toroom temperature, and the reaction was quenched dropwise with MeOH (40mL), then concentrated by rotary evaporation. The material wasazeotroped with MeOH (2×40 mL). The mixture was then diluted with EtOAc(100 mL), and washed with 1 M HCl (2×50 mL), then NaHCO₃ (2×50 mL), thensaturated aqueous NaCl (1×50 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to yield4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.8g) as a clear, light yellow oil that solidified upon sitting.

¹H NMR (CDCl₃) δ (ppm) 7.34-7.22 (m, 3H); 7.19 (dt, J=1.6 Hz, 7.2, 1H);4.73 (s, 2H); 4.32-4.14 (m, 2H); 3.00 (tt, J=4.0 Hz, 12.0, 1H); 2.80 (t,J=11.6 Hz, 2H); 1.78-1.56 (m, 4H); 1.47 (m, 9H).

4-(2-Hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (0.4g, 1.0 mmol, 1.0 eq.) and triethylenediamine (220 mg, 2.0 mmol, 1.4 eq.)were dissolved in DCM (11 mL, 170 mmol). The mixture was cooled at 0° C.under nitrogen, TsCl (290 mg, 1.5 mmol, 1.1 eq.) was added, and themixture was stirred at 0° C. for an additional 60 minutes. The mixturewas diluted with EtOAc (50 mL) and washed with water (2×25 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedby rotary evaporation to yield the title compound (500 mg), which wasused without further purification.

¹H NMR (CDCl₃) δ (ppm) 7.81 (t, J=2.0 Hz, 1H); 7.79 (t, J=2.0 Hz, 1H);7.37-7.32 (m, 4H); 7.25-7.21 (m, 1H); 7.21-7.13 (m, 1H), 5.12 (s, 2H);4.34-4.12 (m, 2H); 2.81-2.61 (m, 3H); 2.45 (s, 3H); 1.70-1.52 (m, 4H);1.48 (s, 9H).

Preparation 24-(2-Methanesulfonyloxymethylphenyl)piperidine-1-carboxylic Acid t-ButylEster

4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g,160 mmol, 1.0 eq.) and THF (100 mL, 1.0 mol) were combined at roomtemperature under nitrogen. 1.0M Borane-THF complex in THF (32.7 mL,32.7 mmol, 2.0 eq.) was added dropwise over 10 minutes (5° C. exotherm,gas evolution). The mixture was stirred at room temperature for 5minutes, then heated at 50° C. for 1 hour. The mixture was cooled toroom temperature, and the reaction was quenched slowly with MeOH (30 mL)(mild exotherm, significant gas evolution), then concentrated by rotaryevaporation. The material was azeotroped with MeOH (2×50 mL). The crudeproduct was dissolved in EtOAc (100 mL, 1 mol), washed with NaHCO₃ (50mL), then saturated aqueous NaCl (50 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo to yield4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.4g) as a clear, light yellow oil that solidified upon sitting.

4-(2-Hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester(50.0 g, 172 mmol, 1.0 eq.) was dissolved in DCM (500 mL, 8000 mmol).The mixture was cooled at 0° C. under nitrogen and methanesulfonicanhydride (44.8 g, 257 mmol, 1.5 eq.) was added in one portion. DIPEA(47.8 mL, 274 mmol, 1.6 eq.) was added dropwise over 5 minutes and themixture was stirred at 0° C. for 90 minutes. Water (400 mL, 20 mol) wasadded and the mixture was stirred for 5 minutes. The phases wereseparated, and the organic layer was washed with water (300 mL), driedover Na₂SO₄, and the solvent removed to yield the title compound (70 g)as a thick oil, which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 7.37-7.43 (m, 3H), 7.31 (d, 1H), 7.22(m, 2H), 5.38 (s, 2H), 4.28 (m, 2H), 2.92-3.10 (m, 1H), 2.92 (s, 3H),2.80-2.92 (m, 2H), 1.63-1.81 (m, 4H), 1.51 (s, 9H).

Example 1 4-[2-(2,4,6-Trifluorophenoxymethyl)phenyl]piperidine

4-[2-(Toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylic acidt-butyl ester (2.1 g, 4.7 mmol, 1.0 eq.) was dissolved in MeCN (46 mL,890 mmol) and added to K₂CO₃ (1.9 g, 14 mmol, 3.0 eq.) and2,4,6-trifluorophenol (1.0 g, 7.0 mmol, 1.5 eq.). The mixture was shakenat 50° C. overnight, then cooled to room temperature. The supernatantwas separated from the K₂CO₃ and other solids. TFA (7 mL, 90 mmol, 20.0eq.) was added to the supernatant and the mixture was shaken overnightat room temperature. The solution was then concentrated to yield a cruderesidue. The residue was dissolved in 5.0 mL 1:1 AcOH/H₂O, then in anadditional 2.0 mL AcOH, filtered and purified by preparative HPLC toyield the title compound as a TFA salt (1.3 g, 97.5% purity). MS m/z:[M+H]⁺ calcd for C₁₈H₁₈F₃NO, 322.13. found 322.2.

¹H NMR (CDCl₃) δ (ppm) 9.83 (br.s, 1H); 9.32 (br.s, 1H); 7.46-7.39 (m,2H); 7.32 (d, J=6.8 Hz, 1H); 7.26-7.21 (m, 1H); 6.76-6.66 (m, 2H); 5.07(s, 2H); 3.69-3.50 (m, 2H); 3.38 (t, J=11.6 Hz, 1H); 3.20-3.02 (m, 2H);2.19 (q, J=12.8 Hz, 2H); 2.12-2.01 (m, 2H).

Synthesis of 4-[2-(2,4,6-Trifluorophenoxymethyl)phenyl]piperidine as aHCl Salt

4-(2-Methanesulfonyloxymethylphenyl)piperidine-1-carboxylic acid t-butylester (27.0 g, 60.6 mmol, 1.0 eq.) was dissolved in McCN (540 mL) andadded to K₂CO₃ (25 g, 180 mmol, 3.0 eq.) and 2,4,6-trifluorophenol (13.5g, 90.9 mmol, 1.5 eq.). The mixture was vigorously stirred at 50° C. for6 hours, removed from the heat, and stirred overnight. The mixture wascooled at room temperature, and diluted with EtOAc (700 mL) and water(700 mL). The phases were separated, and the organic layer was washedtwice with 1.0 M NaOH in water (2×400 mL) and saturated aqueous NaCl(1×400 mL), then dried over Na₂SO₄ and the solvent removed to yieldcrude 4-[2-(2,4,6-trifluorophenoxymethyl)-phenyl]piperidine-1-carboxylicacid t-butyl ester (25.0 g). The crude product was combined with smallerscale runs for a total of 30 g, and purified by chromatography (0-10%EtOAc in hexanes) to yield442-(2,4,6-trifluorophenoxymethyl)phenylpiperidine-1-carboxylic acidt-butyl ester (22.0 g).

The t-butyl ester (22.0 g, 31.3 mmol, 1.0 eq.) was combined with 1.25MHCl in EtOH (250 mL, 310 mmol, 10.0 eq.). The mixture was stirred atroom temperature for 8 hours, then stored at −10° C. over approximately48 hours. Most of solvent was removed by rotary evaporation. To theresulting thick slurry was added EtOAc (80 mL), followed by stirring atroom temperature for 2 hours. First crop was isolated by filtration, andthe filter cake was washed with EtOAc (20 mL) and dried to yield thetitle compound as a hydrochloride salt (8.5 g, >99% purity) white solid.HPLC of the filtrate shows ˜25% area of product. For the second crop,the solvent was removed by rotary evaporation and the resulting solid(˜10 g) was slurried in EtOAc (40 mL), first at room temperature, thenat 60° C., and again at room temperature to yield the title compound asa hydrochloride salt (1.7 g, >99% purity).

Example 2 4-[2-(2,6-Difluorophenoxymethyl)phenyl]piperidine

4-[2-(Toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylic acidt-butyl ester (225 mg, 505 μmol, 1.0 eq.) was dissolved in MeCN (5.0 mL,97 mmol) and added to K₂CO₃ (210 mg, 1.5 mmol, 3.0 eq.) and2,6-difluorophenol (98 mg, 760 μmol, 1.5 eq.). The mixture was shaken at50° C. overnight, then cooled to room temperature. The supernatant wasseparated from the K₂CO₃ and other solids.

TFA (800 μL, 10 mmol, 20.0 eq.) was added to the supernatant and themixture was shaken overnight at room temperature. The solution was thenconcentrated to yield a crude residue. The residue was dissolved in 1.5mL 1:1 AcOH/H₂O, then in an additional 0.3 mL AcOH, filtered andpurified by preparative HPLC to yield the title compound as a TFA salt(115 mg, 95% purity). MS m/z: [M+H]⁺ calcd for C₁₈H₁₉F₂NO, 304.14. found304.2.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1-9. (canceled)
 10. A process for preparing a compound of formula 1:

or a salt thereof, where a is 0, 1, 2, 3, or 4; each R¹ is independently halo or trifluoromethyl; L is a leaving group; and P is an amino-protecting group; the process comprising the steps of: (a′) reacting a compound of formula 4:

or a salt thereof, with a reducing agent to provide a compound of formula 5:

or a salt thereof; and (b′) converting the hydroxyl group of the compound of formula 5 or a salt thereof, into a leaving group, L, to provide a compound of formula 1 or a salt thereof.
 11. The process of claim 10, where a is
 0. 12. The process of claim 10, where L is selected from halogen groups, sulfonic ester groups, and acyloxy groups.
 13. The process of claim 12, where L is a sulfonic ester group having the formula —OS(O₂)—R, where R is —C₁₋₄alkyl or phenyl, and the phenyl group is optionally substituted with —C₁₋₄alkyl, halo or nitro.
 14. The process of claim 13, where L is —OS(O₂)—CH₃ or —OS(O₂)-4-methylphenyl.
 15. The process of claim 10, where the reducing agent is borane dimethyl sulfide complex or borane-tetrahydrofuran complex.
 16. The process of claim 10, where p-toluenesulfonyl chloride or methanesulfonic anhydride is used in step (b′). 17-18. (canceled) 